Chemotherapeutic options are very limited against Mycobacterium abscessus infections. Bedaquiline, a new anti-tuberculosis drug, is effective for the treatment of multidrug-resistant TB. However, little data is available on bedaquiline in treating M. abscessus infections. In this study, we reported the in vitro susceptibility profile of M. abscessus clinical isolates to bedaquiline and investigated the potential molecular mechanisms of decreased susceptibility. A total of 197 M. abscessus clinical isolates were collected from sputum and bronchoalveolar fluid of patients with lung infections. Standard broth microdilution test revealed that bedaquiline exhibited high in vitro killing activity against M. abscessus isolates, with MIC50 of 0.062 and MIC90 of 0.125 mg/L. Whole genome sequencing data showed that no nonsynonymous mutation occurred in atpE, the gene encoding the bedaquiline targeted protein. However, of 6 strains with decreased susceptibility of bedaquiline (MIC=0.5-1 mg/L), 3 strains had nonsynonymous mutations in mab_4384, the gene encoding the repressor of efflux pump MmpS5/MmpL5. qRT-PCR analysis showed that the expression of MmpS5/MmpL5 in the group with decreased susceptibility to bedaquiline were significantly higher than those with medium MIC (MIC=0.125-0.5 mg/L) or low MIC group (MIC≤ 0.062 mg/L). Two isolates with increased MIC didn't show overexpression of MmpS5/MmpL5, which couldn't be explained by known molecular mechanisms. This is the first report showing the association of MmpS5/MmpL5 with decreased bedaquiline susceptibility in M. abscessus clinical isolates, and suggesting the presence of other yet-to-be identified mechanisms for decreased bedaquiline susceptibility in M. abscessus.
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